United States

Background: Central precocious puberty (CPP) results from early reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Four monogenic causes of CPP have been described (KISS, KISS1R MKRN3 and DLK1). Rare loss-of-function mutations of DLK1, a maternally imprinted gene located on chromosome 14q32.2, were identified in families with CPP. Both inherited or de novo DLK1 mutations were described in these affected families.
Objective: To investigate genetic abnormalities in the DLK1 in a French cohort of patients with idiopathic CPP.
Patients: Genomic DNA was obtained from 122 patients (99 girls and 23 boys) with sporadic or familial CPP. Automatic sequencing of the coding regions of DLK1 gene (5 exons, using Sanger method) was performed in all cases, including 91 familial and 31 sporadic cases.
Results A pathogenic heterozygous variant in the DLK1 gene (c.372C&gt;A p.Cys124Ter (rs749564412) was identified in a girl with sporadic CPP associated with overweight. This nonsense mutation was considered rare (gnomAD total population 1/251,082) and it was located in the third EGF-like repeat domain in the extracellular region. The affected girl had progressive breast development at 4.5 years and accelerated growth velocity. She had breast development Tanner stage 4 at 5.5 years and bone age (BA) was 6 yr. Her height was 114.5 cm and BMI 18.16 (BMI Z-score = 2.48). Basal LH and FSH was 0.6 IU/L and 5.7 IU/L, respectively. GnRH-stimulated LH and FSH peaks were 14 IU/L and 18 IU/L, respectively, with LH: FSH ratio of 0.77. Other hormonal results were normal (estradiol: 11 pg/mL; ACTH: 11 pg/mL; IGF-1: 235 ng/mL; cortisol: 77 ng/mL). Brain MRI was normal. Pelvic ultrasound revealed uterus length: 49 mm, mucosal thickness of 4 mm, ovaries 20 and 25 mm with follicles less than 10 mm. She was treated with a depot GnRH analog (triptorelin). The DLK1 variant was inherited from her asymptomatic father who had a height of 181 cm. Familial history of CPP history was denied.
Conclusion: DLK1 loss-of-function are rare genetic cause of familial or sporadic CPP. Novel genetic findings in this factor reinforce its role in the physiopathology of the premature HPG axis reactivation and precocious sexual development in humans.

ENDO 2022

A novel nonsense mutation in Delta-like non-canonical Notch ligand 1 gene (DLK1) in a French girl with central precocious puberty

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Background: Central precocious puberty (CPP) results from early reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Four monogenic causes of CPP have been described (KISS, KISS1R MKRN3 and DLK1). Rare loss-of-function mutations of DLK1, a maternally imprinted gene located on chromosome 14q32.2, were identified in families with CPP. Both inherited or de novo DLK1 mutations were described in these affected families.
Objective: To investigate genetic abnormalities in the DLK1 in a French cohort of patients with idiopathic CPP.
Patients: Genomic DNA was obtained from 122 patients (99 girls and 23 boys) with sporadic or familial CPP. Automatic sequencing of the coding regions of DLK1 gene (5 exons, using Sanger method) was performed in all cases, including 91 familial and 31 sporadic cases.
Results A pathogenic heterozygous variant in the DLK1 gene (c.372C>A p.Cys124Ter (rs749564412) was identified in a girl with sporadic CPP associated with overweight. This nonsense mutation was considered rare (gnomAD total population 1/251,082) and it was located in the third EGF-like repeat domain in the extracellular region. The affected girl had progressive breast development at 4.5 years and accelerated growth velocity. She had breast development Tanner stage 4 at 5.5 years and bone age (BA) was 6 yr. Her height was 114.5 cm and BMI 18.16 (BMI Z-score = 2.48). Basal LH and FSH was 0.6 IU/L and 5.7 IU/L, respectively. GnRH-stimulated LH and FSH peaks were 14 IU/L and 18 IU/L, respectively, with LH: FSH ratio of 0.77. Other hormonal results were normal (estradiol: 11 pg/mL; ACTH: 11 pg/mL; IGF-1: 235 ng/mL; cortisol: 77 ng/mL). Brain MRI was normal. Pelvic ultrasound revealed uterus length: 49 mm, mucosal thickness of 4 mm, ovaries 20 and 25 mm with follicles less than 10 mm. She was treated with a depot GnRH analog (triptorelin). The DLK1 variant was inherited from her asymptomatic father who had a height of 181 cm. Familial history of CPP history was denied.
Conclusion: DLK1 loss-of-function are rare genetic cause of familial or sporadic CPP. Novel genetic findings in this factor reinforce its role in the physiopathology of the premature HPG axis reactivation and precocious sexual development in humans.

technical paper

Thyroid cancer will become 4th most common cancer in women by 2030. Thyroid cancer is the most prevalent endocrine malignancy of women with an age-standardized rate of 10.1/100,000 while in men it is 3.1/100,000.
The microenvironment of thyroid cancer has a high degree of immune invasion, characterized by the presence of T effector (Teff, CD4, and CD8) cells. In our previous study based on 127 human FNA thyroid samples, we reported a dominant T cell species characterized by the deficiency of CD4 and CD8 expression (CD3+CD4-CD8-) Double Negative (DN) T cells, seem to have a regulatory function towards thyroid cancer immune tolerance (1-3).
Here, in another cohort study (46 patients), FNAs of thyroids showed that DN T-cells were significantly more abundant in lymphocytic infiltrates of thyroid cancer patients (post-operatively confirmed diagnosis by an academic pathologist), and if the DN T cell population exceeded our defined threshold (>9.14%), it indicated a high likelihood of cancer presence (96.6% sensitivity, 95% CI, 0.915 to 1.000). Conversely, DN T cells below the threshold (<9.14%) provide 100% specificity in predicting benignity of thyroid nodules.  This study identifies DN T cell quantification as an accurate rule-out test. The high specificity of the test is promising since it abolishes false-positive diagnoses and unnecessary surgical procedures. Current molecular diagnostic testing, based on the identification of tumor gene mutations in FNA samples usually reduces the risk of cancer rather than guarantee the absence of cancer which leads to 70% of unnecessary thyroidectomies.
The present study proposes DN T cell quantification as a diagnostic signature for thyroid cancer. Its integration with RNA transcriptomics may provide a simplified technology for thyroid cancer screening and active surveillance.
References
1.  Imam S, Paparodis R, Sharma D, et al. 2014 Lymphocytic profiling in thyroid cancer provides clues for failure of tumor immunity. EndocrRelat Cancer 21.
2.  Imam S, Dar P, Paparodis R, et al. 2019 Nature of coexisting thyroid autoimmune disease determines success or failure of tumor immunity in thyroid cancer. J Immunother Cancer 7.
3.  Imam S, Jaume J C 2021 Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer. International Application No. PCT/US2021/012057, Publication Number WO/2021/138661

Decoding Cancer Immunoediting of Tumor Microenvironment Provides Immunogenomic Marker for Thyroid Cancer Screening

Progressive metastasis is the proximate cause of cancer-related mortality for the majority of patients with solid tumors. Identifying both drivers, and gatekeepers of late stage progression (metastasis progression suppressors; MPS) is crucial to improve biomarkers and treatments. We previously identified Regulator of Calcineurin 1.4 (RCAN1.4) as a MPS gene in thyroid cancer that functions in part through overexpression of the cap-n-collar transcription factor NFE2L3 (NRF3).  However, the mechanisms for RCAN1.4 loss in thyroid cancer, and whether or not this is reversible, had not be addressed. Because the RCAN 1.4 promoter contains CG rich regions reported to be hypermethyalated in other tissues, we hypothesized that RCAN 1.4 downregulation in thyroid cancer was similarly regulated. Studies were performed in both cell lines and de-identified human papillary thyroid cancer (PTC) tumor and normal tissue pairs from our Endocrine Neoplasia Repository tumor bank. Five thyroid cancer cell lines (TPC1, FTC133, BCPAP, C643, and 8505C) with different genetic drivers were selected based on low expression of RCAN 1.4. To determine if lines display methylation-regulated expression of RCAN 1.4, cells were treated with 1-10uM decitabine, a DNA methyl transferase inhibitor. In all cell lines, RCAN1.4 mRNA and protein levels increased with decitabine treatment, consistent with hypermethylation. Analysis of the literature and in silico analysis of the RCAN 1.4 gene identified CG rich regions as putative methylation targets in the proximal promoter and in intron 1. Using two different methods; 1) isolation of MseI-digestion DNA fragments using CpG MethylQuest beads followed by qPCR and 2) methylation-specific PCR (MSP) of bisulfite-modified DNA , hypermethylation of the intron 1 CG rich region was identified. There was no evidence of hypermethylation of the CG rich region of the proximal promoter. Methylation of the two regions also was assessed on 18 pairs PTC and adjacent normal tissues. Similar to the cell lines, hypermethylation was identified at intron 1 of RCAN 1.4 in PTC versus normal tissues. QRT-PCR results confirmed lower levels of RCAN1-4 mRNA in the PTC vs normal tissue. These samples also demonstrated increased NRF3 expression versus normal tissue. Taken together, these data demonstrate that RCAN 1.4 is downregulated in thyroid cancer cells and human PTCs by hypermethylation of CG rich regions in intron 1 and that this effect is reversible using demethylating agents.

The RCAN 1.4 Metastasis Progression Suppressor Gene is Hypermethylated at Intron 1 and Downregulated in Papillary Thyroid Cancer

Background: Integrins are cell adhesion receptors consisting of 24 transmembrane heterodimers generated from a combination of 18α integrin and 8β integrin subunits. A subset of integrins consists of receptors recognizing Arg-Gly-Asp (RGD) peptide motifs. One of the RGD-recognizing receptors is integrin αvβ3 that has been recently shown to play a role in neovascularization and progression of several cancers. Radiolabeled RGD analogs have emerged as potential imaging and therapeutic options in cancers characterized by a high expression of integrin αvβ3. Therefore, the aim of this study was to establish the expression of integrin αvβ3 in thyroid cancer (TC).
Methods: We analyzed the mRNA expression of integrin αvβ3 in 496 BRAF-like and RAS-like human TC tissue samples, including 65 paired samples of tumor vs normal tissue based on The Cancer Genome Atlas. We assessed the protein expression of integrin αvβ3 in 70 TC tissue samples and 10 normal thyroid tissues, as well as in 14 TC cell lines. BRAF-like or RAS-like tumor status was determined by BRS score based upon standard expression profiles ranging from -1 to 0 for BRAF-like cancer and 0 to 1 for RAS-like tumors. The association between BRS and αvβ3 expression was tested using the Spearman correlation coefficient (r). T-tests and paired T-tests were used to compare the continuous variables between the two groups as appropriate, and Kruskal-Wallis test was used for multiple group comparisons with an adjusted p-value of ≤ 0.05 as statistically significant.
Results: αv integrin subunit mRNA expression was significantly higher in TC than normal thyroid (log fold change 0.3, p=0.001), while the expression of the β3 subunit was similar between paired normal and malignant samples (log fold change -0.2, p=0.30).  BRAF-like tumors were characterized by a higher mRNA expression of αvβ3 integrins as documented by a moderate negative correlation between BRS and αv (r=-0.5, p<0.001) as well as β3 (r=-0.27, p<0.001). Consistently, the BRAF-like TC cell lines OCUT2 (BRS=-1), TPC1 (BRS=-0.4), K1 (BRS=-0.29), as well as Hurthle cell TC cell line XTC1 (BRS=-0.46), were characterized by the highest αvβ3 mRNA and/or protein expression. Immunostaining revealed αv expression in all malignant samples, with classic papillary TC characterized by the highest expression as compared with follicular TC (p<0.001), poorly-differentiated TC (p=0.006) and normal thyroid (p<0.001). β3 protein expression had lower intensity than αv integrin and was present in 31.8% of papillary TC, 15% of follicular TC and was not detected in poorly-differentiated TC nor normal thyroid.
Conclusions: TC is characterized by a differential expression of αvβ3 integrin, which is particularly high in the most common type of TC - BRAF-like papillary TC. The αvβ3 integrin could potentially serve as a molecular target for imaging and therapy with radiolabeled RGD analogs in TC.

Integrins as Potential Molecular Targets in Thyroid Cancer Imaging and Therapy

Thyroid cancer is the most prevalent endocrine malignancy and is estimated to have affected 52,890 individuals in the United States in the year 2020. Papillary thyroid cancer (PTC) accounts for up to 80% of all thyroid cancer diagnoses. Within PTC, BRAFV600E is the most common mutation in adults and the second most common mutation in pediatrics. While there are several validated human thyroid cancer cell lines harboring BRAF mutations, no pediatric derived cell line has been established to date, limiting generalizations in pediatric disease. Patient-derived pre-clinical models are valuable tools but are limited due to their need to be studied in vitro or in an immunocompromised host. However, in vivo mouse models recapitulate the complex interactions between tumor cells, the immune system, and components of the microenvironment, allowing more comprehensive investigation of thyroid oncogenesis and response to therapy. In this study we describe a new subcutaneous mouse model that can be used to understand differences between pediatric onset and adult onset PTC.
We have developed multiple independent, congenic murine cell lines from different stages of thyroid cancer progression. Two independent BRAFV600E-driven cell lines harboring the same genetic mutations were utilized in this study, one representing a well-differentiated tumor (WD) and one representing a poorly-differentiated tumor (PD). Despite coming from different stages of disease, both cell lines showed similar expression of the thyroid specific genes: Pax8, Ttf1, Tg, and Slc5a5, but expression of Pax8, Tg, and Slc5a5 was lower compared to WT thyrocytes. Activation of the Pi3Kinase pathway and the Akt Pathway were assessed via western blot analysis. The WD cell line had increased pERK activation compared to the PD cell line, and the PD cell line had increased pAKT compared to WD cell line.
Both cell lines were injected subcutaneously into the hind flank of Wt SJV129 mice of pediatric age (4-5 weeks) and adult age (20-22 weeks). These animals were monitored for 10 weeks post injection. While the PD cell line developed tumors at approximately the same rate and penetrance in both age groups, tumors reached end point more rapidly in the adult cohort. Adult hosts injected with the WD cell line developed tumors more rapidly than in pediatric hosts, however, tumors receded in both cohorts.
While adult and pediatric thyroid cancer share common driving mutations, there are distinct differences in disease pathogenesis between these patient populations. There are known differences in the immune system, metabolism, and other variables between pediatrics and adults. However, it is unknown what causes the difference in PTC pathogenesis between pediatric versus adult patients. We believe these new models provide a great opportunity to evaluate the role of age in PTC development and progression.

Novel Murine Models of BrafV600E driven Papillary Thyroid Cancer

Background: Thyroid cancers (TC) are divided into BRAF-like and RAS-like tumors based on their molecular signature. The mTOR (mammalian target of rapamycin) signaling pathway is commonly activated in RAS-like tumors. Oncogene-driven signaling pathways are involved in the regulation of intracellular metabolism, including glycolysis and oxidative phosphorylation (OXPHOS). There is inadequate information on the role of mTOR signaling in the regulation of TC metabolism. The purpose of this study was to determine the association between mTOR signaling and mitochondrial respiration in TC.

Methods: We conducted an in vitro study using 4 TC cell lines (2 BRAF-like, 2 RAS-like) characterized by variable activation of mTOR signaling pathway, as documented by immunoblotting to quantify a ratio of p-mTOR/mTOR. OXPHOS was measured through oxygen consumption rate (OCR) of TC cells by the Seahorse XF Cell Mito Stress Test Assay. Standard MTT assay was performed to evaluate cell proliferation. A specific mTOR inhibitor (rapamycin) as well as an mTOR activator (leucine) were used for functional studies. The association between OCR and p-mTOR/mTOR was calculated by Pearson correlation coefficient (r). The one-way Anova or Kruskal-Wallis test were used for between group comparisons, as appropriate. P-values of ≤ 0.05 were considered statistically significant.

Results: The baseline activation of mTOR signaling in TC cells correlated with baseline (r=0.75, p=0.04) and maximum OCR (r=0.91, p=0.01). In addition, the RAS-like cell lines with the highest activation of mTOR showed considerable response after inhibition of mTOR with rapamycin by inhibiting baseline OCR (FTC133: 6320 ± 1531 vs 3368 ± 651 pmol/min/mg, p=0.01; THJ29T: 4484 ± 514 vs 3067 ± 620 pmol/min/mg, p=0.047), while the TC cell lines with minimal baseline mTOR activation did not show change in mTOR phosphorylation status nor basal OCR after rapamycin treatment (TPC1: 1817 ± 201 vs 1974 ± 336 pmol/min/mg, p>0.99, BCPAP: 1051 ± 162 vs 1130 ± 228 pmol/min/mg, p>0.99). Treatment with rapamycin significantly reduced cell proliferation rates in all examined cells. On the other hand, treatment with the mTOR activator leucine increased both mTOR phosphorylation and basal OCR in TC cell lines characterized by minimal baseline mTOR activation (TPC1: 1778 ± 280 vs 2372 ± 249 pmol/min/mg, p=0.004, BCPAP: 1581 ± 603 vs 2064 ± 560 pmol/min/mg, p=0.04), but did not significantly increase OCR further in cell lines with high baseline mTOR activation and OXPHOS rate  (FTC133: 4512 ± 683 vs 5355 ± 870 pmol/min/mg, p=0.27; THJ29T: 3881 ± 880 vs 4764 ± 1273 pmol/min/mg, p=0.14).

Conclusion: mTOR signaling is associated with the regulation of mitochondrial respiration as its inhibition decreases OXPHOS rate, while its activation results in increased mitochondrial respiration. The change in mitochondrial respiration might be one of the mechanisms of the growth inhibition caused by medications targeting mTOR signaling in TC.

mTOR Signaling is Associated with Regulation of Mitochondrial Respiration in Thyroid Cancer

The identification of thyroid tumors with the potential for poor evolution is a major concern, as current management can range from simple active surveillance to aggressive therapeutic measures. MicroRNAs are small non-coding RNAs that play a key role in the regulation of gene expression and therefore in the pathogenesis and progression of different types of cancers. Here we employed several bioinformatics tools to investigate deregulated miRNAs in the lymph node metastasis (LNM) of two different types of thyroid tumors. Using thyroid cancer RNA-seq data available on Gene Expression Omnibus (GEO), we identified 14 common deregulated miRNAs in LNM of both medullary and papillary thyroid carcinomas, three of them still negatively deregulated when compared to their respective primary tumor: miR-199a-3p, miR-199a-5p, and miR-148a-5p. Public data available on TCGA confirmed the downregulation of miR-148a-5p in LNM and tumors with advanced AJCC stage. Looking at their predicted target genes, ITGA3, PVRL1 (also called NECTIN1), SNN, and FBXO28 genes were confirmed as positively deregulated in LNM papillary thyroid carcinomas when compared to normal tissues. Public data available on TCGA once again confirmed higher expression of the ITGA3 gene in LNM, larger and invasive tumors (T4a), and stage III and IV. Similar results were observed for PVRL1 (NECTIN1) and FBXO28, but not for SNN. These bioinformatic analysis findings suggest that miR-199a-3p, miR-199a-5p, and miR-148a-5p dysregulation, leading to epithelial-mesenchymal transition and cell adhesion failure, are associated with thyroid tumors' LNM.

Identification of MicroRNAs Critical to the Lymph Node Metastatic Process of Thyroid Cancer

Background: The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR.
Methods: Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline.
Results: As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m², body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment.
Conclusions: Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634).

Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide

Background: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental condition, characterized by hyperphagia, obesity, hormone deficiencies and behavioral/psychological manifestations. DCCR is under investigation as a treatment for hyperphagia in PWS through its actions on hypothalamic circuits involved in appetite regulation including NPY neurons and central inhibition of DMV neurons to improve insulin sensitivity. In addition to these effects, DCCR acts on pancreatic beta cells, to reduce glucose stimulated insulin secretion, which might have additional effects to reduce fat deposition in adipocytes, serum leptin concentrations and insulin resistance.
Objectives and methods: This analysis characterized changes in hormonal and cardiometabolic parameters in patients with PWS receiving oral daily DCCR.  125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (analysis at 52 weeks). The target DCCR dose for these studies was ≥3.3 mg/kg with an optimal dose of 4.2 - 5.8 mg/kg. Overall, 103 patients received DCCR (100-525 mg/day) for 52 weeks. For all parameters, the baseline measurement was defined as (immediately prior to) start of DCCR treatment.
Results: Serum leptin, insulin, and HOMA-IR were significantly reduced following 52 weeks of DCCR administration.  Results are expressed as Least square (LS) mean change from baseline [Standard Error (SE)]. There were significant decreases in: Leptin (ng/mL) = ‑11.08[1.26], p<0.001; Insulin (μIU/mL) = ‑2.5[0.69], p<0.001; and HOMA-IR = -0.5 [0.17], p=0.003.  Serum adiponectin (µg/mL) was significantly increased: 1.82[0.41], p < 0.001.  Fat mass measured by DXA was stable at 52 weeks.
Conclusions: The reductions in fasting leptin, insulin and HOMA-IR, and the increase in adiponectin with prolonged DCCR treatment in the absence of reductions in total body fat are consistent with improved insulin sensitivity that may also reflect improvement in leptin sensitivity and healthier body fat distribution, such as reduced visceral adiposity. This could result from both direct pancreatic and hypothalamus-to-periphery actions of DCCR. It remains to be determined if such beneficial metabolic changes also result in reduced systemic inflammation and cardiovascular health.
DCCR administration was associated with significant reductions in leptin, insulin, and HOMA-IR, increases in adiponectin and stabilization of body fat. These and other changes in cardiometabolic parameters suggest that DCCR may have long term health benefit in patients with PWS.

Hormonal and Cardiometabolic Changes Associated with Diazoxide Choline Extended-Release (DCCR) Tablets in Patients with Prader-Willi Syndrome

Objective: To determine the association of anti-obesity medications (FDA-approved and off-label) with weight loss maintenance over 3-5 years.
Methods: We performed a retrospective observational study of adults 18-75 years treated for overweight/obesity at a tertiary academic weight management center with an initial visit between April 1st, 2014 and April 1st, 2016. We excluded patients who had a period of follow-up less than 2.5 years or a gap in follow-up of greater than 2 years. Patients who had bariatric surgery, pregnancy, or a medical condition predisposing them to weight loss during the study were also excluded. We extracted key demographic data, medical history, and weight at each visit. Anti-obesity medication (AOM) start date and end date was determined through chart review with attention to patient self-reporting of medication adherence to calculate total exposure to each AOM. We used the weight loss maintenance definition of weight regain ≤ 3% of the nadir weight.
Results: A total of 428 patients met inclusion criteria for the analysis and were followed for a mean of 4.4 years. The mean age was 50.9 years, 73% were female, and median initial BMI was 34.3 kg/m². Weight categories were as follows: 19% overweight, 35% class 1, 25% class 2, and 20% class 3 obesity. In addition, 16% had diabetes and 36% had prediabetes.
The median nadir BMI was 25.6 with a median maximum weight loss of 14.7%. The median time to achieving nadir weight was 1.9 years. Average weight change from the initial to final visit was -10.6% (-10.9 kg), with a final visit median BMI of 27.4. The proportion of patients who achieved ≥5%, ≥10%, ≥15%, and ≥20% total weight loss was 70.8%, 48.1%, 30.1%, and 16.8%, respectively. During the 4.4 years the patients were followed, weight regain following the nadir weight was 6.3%. At the last observation, 40.2% of all patients had maintained their maximum weight loss.
The mean number of AOMs trialed throughout the duration of the study was 4.2. At the final visit, a mean of 2.5 AOMs were being taken. The most common medications observed at the final visit alone or in combination were metformin (76.2% of patients), phentermine (31.1%), topiramate (30.8%), bupropion (29.9%), and semaglutide (24.5%).
Conclusion: Long-term weight loss of 10.6% was observed over 3-5 years in adults with overweight/obesity who were managed with pharmacotherapy. This study demonstrates clinically significant long-term weight loss maintenance can be achieved with pharmacotherapy and lifestyle interventions.

Long-term Weight Loss Maintenance with Obesity Pharmacotherapy: a 5-Year Retrospective Study

Background: Satiety is the result of postprandial physiologic events that determine the timing for the next meal by inhibiting the sensation of hunger. It is orchestrated by the brain-gut-axis, with gastric emptying and accommodation being key components of satiety and appetite sensations. Several indices have been used to quantify satiety. Longer time to empty 50% of the stomach content (GEt1/2) during a gastric emptying for solid study (GES), and lower SQ for fullness, lower SQ for satisfaction, and higher SQ for hunger after a meal challenge measured by visual analog scales (VAS) are all associated with prolonged satiety and are therefore protective against caloric overconsumption and to the development of obesity. Although obesity prevalence is higher in female compared to male subjects, there is little data on how sex affects biological indices of satiety.
Methods: This retrospective cohort study included patients with overweight and obesity who underwent anthropometric measurements, body composition evaluation, and satiety tests. After an 8-hour overnight fast, patients were provided a radiolabel breakfast (320kcal, 30% fat) to measure GES by scintigraphy over 4 hours and appetite sensations. We measured appetite sensations (hunger, fullness, and satisfaction) with 100-mm VAS every 30 minutes for 4 hours at baseline (before eating breakfast, i.e. VAS0') and after breakfast (VAS30' to VAS240'). The SQ for each appetite sensation was calculated with the following formula: (VAS0' – VAS30')/320. We performed univariate and multiple regression analyses to estimate the contribution of biological and anthropometric variables to GEt1/2.
Results: We included 743 subjects: 557 females (75%), mean age 40±11 years, mean BMI 33±8kg/m². Compared to males, female participants had significantly higher BMI and lower height, weight, waist-to-hip ratio (W/H), and percentage lean mass (%LM). Compared to males, female participants had a slower GEt1/2 (123 vs. 98 minutes, p<0.0001), lower SQ for fullness (-15 vs. -12 mm, p=0.008), and lower SQ for satisfaction (-14 vs. -11 mm, p=0.01). Females had higher but not significant SQ for hunger. On univariate analysis, height, BMI, and %LM had a negative but significant correlation with GEt1/2 (R=-0.3, p<0.0001; R=-0.1, p=0.02; and R=-0.2, p=0.0003; respectively). On multiple regression analysis, when taking into consideration age, sex, height, W/H, and %LM, only sex (parameter estimate [PE]=6.8, p=0.02), height (PE=-82, p=0.0005), and W/H (PE=49, p=0.004) were independent predictors of GEt1/2.
Conclusion: This study highlights the sex differences in indices of satiety measured by GEt1/2 with a GES, and by SQ for hunger, fullness, and satisfaction with VAS. Sex is a strong independent predictor of GEt1/2. These observations highlight the importance of considering sex as a variable to understand the pathophysiologic mechanisms involved in obesity's heterogeneity.

A novel nonsense mutation in Delta-like non-canonical Notch ligand 1 gene (DLK1) in a French girl with central precocious puberty

Downloads

Next from ENDO 2022

Decoding Cancer Immunoediting of Tumor Microenvironment Provides Immunogenomic Marker for Thyroid Cancer Screening

Similar lecture

Clinical, Hormonal and Genetic Characterization of Familial Central Precocious Puberty

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES